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The choice of viral load endpoint in early phase trials of COVID-19 treatments aiming to reduce 28-day hospitalization and/or death

  1. Author:
    Mateja,Allyson [ORCID]
    Chu,Eric
    Murray, Thomas A [ORCID]
    Bramante, Carolyn T
    Moser, Carlee [ORCID]
    Givens, Naomi
    Abdelghany, Mazin [ORCID]
    Blair, Chris
    Chen, Shuguang
    Lat, Prince Kumar
    Harari, Ofir
    Kallewaard, Nicole L
    Macpherson, Lisa Farmer
    Boulware, David R [ORCID]
    Suñer, Clara
    Mitjà, Oriol
    Adam, Stacey J [ORCID]
    De Gruttola, Victor
    Hughes, Michael D
    Rubin, Daniel
    Smith, Davey M [ORCID]
    Potter, Gail E [ORCID]

  2. Author Address

    Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA., General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MD, USA., Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA., GlaxoSmithKline, Stevenage, United Kingdom., Gilead Sciences, Inc., Foster City, CA, USA., Redwood AI, Vancouver, BC, Canada., Eli Lilly and Co, Indianapolis, IN, USA., Skin Neglected Tropical Diseases and Sexually Transmitted Infection section, Fight Infectious Diseases Foundation, University Hospital Germans Trias i Pujol, Badalona, Spain., ISGlobal, Hospital Cl 237;nic - Universitat de Barcelona, Barcelona, Spain., Infectious Diseases Department, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain., The Foundation for the National Institutes of Health, North Bethesda, MD, USA., Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA., Harvard TH Chan School of Public Health, Boston, MA, USA., Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA., Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA, USA., Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.,
    1. Year: 2025
    2. Date: Jun 03
    3. Epub Date: 2025 06 03
  2. Journal: The Journal of Infectious Diseases
  4. Type of Article: Article
  1. Abstract:

    Virologic endpoints are used in Phase 2 trials for COVID-19 therapeutics, but they have not been established as surrogates for clinical endpoints. No meta-analysis using individual participant data (IPD) has been undertaken to identify viral load outcomes for which treatment effects are best associated with effects on hospitalization/death. This meta-analysis combined IPD from 23 COVID-19 treatment vs. control comparisons to calculate R2, a surrogacy measure quantifying the relationship between the treatment effect on 28-day hospitalization/death and the treatment effect on the surrogate. R2 ranges from 0-1, with a strong relationship =0.72, moderate 0.49< R2< 0.72, and weak =0.49. We estimated R2 for various viral load outcomes at Days 3, 5, and 7, including change-from-baseline, slope, average area under the curve minus baseline (AAUCMB), and a change of at least 0.5 log10 copies/mL from baseline to Day 3. R2 was numerically highest for the change-from-baseline to Day 3 (0.53 [0.26, 0.79]), slightly lower for change-from-baseline to Day 5 (0.49 [0.24, 0.75]) and numerically lower for change-from-baseline to Day 7 (0.40 [0.15, 0.65]). All were statistically significant. Our study is the first to use IPD, allowing us to evaluate viral load collected on various study days as a surrogate to clinical outcomes. Change in log10(viral load) from baseline to Day 3 or Day 5 are moderate surrogates for 28-day hospitalization/death and suitable primary endpoints in Phase 2 clinical trials and are preferred over change-from-baseline to Day 7. Slope and AAUCMB require more calculation but didn't improve prediction so aren't recommended. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2025.

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External Sources

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  2. DOI: 10.1093/infdis/jiaf282
  3. PMID: 40461945
  4. PII : 8156441

Library Notes

  1. Fiscal Year: FY2024-2025
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